We have evidence, as has also been discussed, that treatment of visualized lesions that we can see on a PSMA PET with metastasis-directed therapy can meaningfully shift the trajectory of disease. And we also have evidence that medications like darolutamide or other AR pathway inhibitors can improve outcomes for people with prostate cancer in multiple disease settings. So the purpose of this trial was to understand whether adding darolutamide to ADT in a high-risk biochemical recurrent population with PSMA PET-positive disease could prolong the time to progression of disease as measured by PSMA PET/MFS. And I would say importantly that metastasis-directed therapy has been incorporated into this trial. I think that it would be a difficult trial to do without that incorporation.
So difficult to read here because there are many criteria in terms of the inclusion criteria, but essentially patients have to have had either primary surgery or radiotherapy. They have to have a maximally treated pelvis, meaning that if they had surgery, they have to have had salvage radiation therapy after that surgery.
If they had radiation, obviously they would have already had the radiation. They have to have high-risk biochemical recurrence as defined by a PSA doubling time of 12 months or less, and they have to have PSMA-positive disease. This study recruited fully 970 patients, randomized them to treatment with all patients receiving SBRT or surgical treatment to PSMA PET-positive lesions, and everyone received ADT plus darolutamide or placebo for a total duration of 24 months. And as you can see on the right, radiographic progression-free survival by PSMA PET assessed by blinded central review is the primary endpoint. Very, very importantly, as I mentioned, maximally treated pelvis for these patients, and they all had to have metastasis-directed therapy.
The study endpoints, as I said, primary radiographic progression-free survival by PSMA PET. These are PET scans that are occurring every six months on study. Simultaneously, patients are getting conventional imaging on study, both at baseline and every six months. A key secondary endpoint of the study is metastasis-free survival by conventional imaging. There are additional endpoints. I think in order to ensure the potential validity of this new primary endpoint, additional endpoints can add to the data set, and some of these include time to castration-resistant prostate cancer, which would be a PSA or radiographic progression, time to initiation of first subsequent therapy, and importantly, this includes the delivery of metastasis-directed therapy and/or systemic therapy, time to local regional progression by PSMA PET. So this would be a pelvic or a local prostate bed recurrence, because the MFS endpoint by PSMA PET required an extrapelvic metastatic lesion, as well as overall survival and safety and tolerability assessments, including patient-reported outcomes and time to complications.
So when it comes to the definition of PSMA PET progression, again, this is an extrapelvic M1 lesion on PSMA PET. This is not an increase in SUV or an increase in uptake in something that is already present. This is not a pelvic progression of disease. If patients do experience progression by conventional imaging, which would be CTs and bone scans for most patients, PSMA PET imaging continues to occur at that every six month interval until at least one new lesion is identified on PSMA PET. And if treatment is delivered per local standards, the reason for treatment has to be documented, whether that's PSA progression, local progression, or toxicity, needing to discontinue therapy. And there's a very strong recommendation for patients to avoid treatment based on PSA progression alone without PSMA PET progression, though of course it is always important to do what's right for patients and one would never withhold that treatment if it's necessary.
Important considerations in ongoing discussions and discussions that happened at the development of this trial included things like a blinded central review with a specific charter for the nuclear medicine physicians who are engaged in reviewing the PSMA PET imaging. There are three, so that there can be adjudication if there is disagreement. There's a locked baseline read, no retrospective change in a read based on subsequent PET findings. In clinic, sometimes we say, "Oh, that thing is probably a false positive," but then if there is a PSMA PET that comes in the future, we can say, "Oh, maybe it was actually positive and maybe we'll need to act on that." That's not happening. And I think also importantly, there's a blind or a block between the people that are reading the conventional imaging, the people that are reading the nuclear medicine scans, and actually all of the clinical data. So PSA and symptoms cannot be considered as people are reviewing the imaging.
Conventional imaging and PET imaging occurs on the same schedule, and we do have to continue the PET imaging even if the conventional imaging progression is met. Very, very important. And I think that this simultaneous delivery of these imaging modalities will help us to develop an understanding of what it looks like to progress in one imaging modality versus another, and how do we crosswalk between these additional endpoints like time to next therapy, time to CRPC, and other progression endpoints are critical, again, in establishing a totality of the data. Challenges have been mentioned already, and we are all very aware of them in clinic. The definition of PSMA PET progression for this study was developed based on consensus standards and the best evidence at the time that we came up with it. This was before Prostate Cancer Working Group 4 definition came out, and a change in the primary endpoint in a regulatory directed study or approval, a study that is developed for regulatory approval is really not possible and not something that we want to do at this time.
Current practices for metastasis-directed therapy do vary by region, so understanding how that may differ around the world, given that this is an international study, is not easy, and there are definitely challenges in interpreting different patterns of progression and how we might address each one. Just as an example from my clinic, and this is not a real scan, this is an AI developed scan, which is pretty good. In any event, a patient could have, or in my clinic had an essential read or my own radiologist read without sclerotic activity on a CT correlate for ... There was no CT correlate on a rib lesion. There was really an intermediate SUV uptake. It was deemed to be a false positive, but on imaging 18 months later, there was increased SUV uptake in the same lesion, extension of that lesion by PSMA avidity, no change in the CT, and the PSA was rising.
So what do we do in clinic? How should this be handled? We don't necessarily even know in clinic, but certainly that's going to be a challenge in a study like this. So just mentioning that these are known, acknowledged, and something that we're trying to deal with. There are multiple other studies that are in this space, different approaches for different studies. The PRIMORDIUM study is a study that is looking at a similar biochemical recurrent setting, but these patients have not had salvage radiotherapy to the pelvis, so they are getting that plus metastasis-directed therapy, plus either ADT and apalutamide versus ADT and placebo, and they are following for a PSMA PET metastasis-free survival, one primary new lesion primary endpoint. So we will see what we see. And a separate study that I think we all know as well, PSMA-DC for patients with high-risk biochemical recurrence and PSMA PET-positive disease who are receiving SBRT to all metastatic lesions with or without lutetium-177, PSMA-617. Again, we'll see what we see, but conventional imaging MFS is the primary endpoint here.
So in summary, strategies to strengthen the validity of a PSMA PET MFS endpoint can reduce the risk of this endpoint. Randomization and large sample sizes can balance difficult to interpret cases between treatment groups. Blinded trial with central imaging review does reduce bias. And a rigorous collection of additional endpoints like MFS by conventional imaging, time to first subsequent therapy, et cetera, provide supporting evidence of this endpoint or an endpoint that you choose. PSMA PET is part of the treatment algorithm. And I think that if we fail to incorporate this, we really reduce or increase the risk of loss of trial integrity, reduce the ability to interpret our results, and then this can lead to challenges when integrating our results into practice. So we're all facing this problem and hopefully we'll work together to find a solution.